Hypoxia, a pathological condition deprived of adequate oxygen supply, is a hallmark of various intractable diseases such as cancer, cardiopathy, ischemia, rheumatoid arthritis, and vascular diseases. For example, experimental and clinical studies have demonstrated that tissue partial pressure of oxygen (tPO2), measured in ischemic stroke and cancer, is near zero mm Hg which is substantially lower than that in the normal tissue (˜30 mm Hg). Since hypoxia is involved in many aspects of the biology of diseases, it significantly affects the therapeutic responses to the diseases. In particular, hypoxia is a negative factor for cancer therapy because it contributes to chemoresistance, radioresistance, angiogenesis, invasiveness, and metastasis. Nevertheless, owing to its unique features which are rarely found in the normal tissue, hypoxia is emerging as the primary target for developments of diagnostic agents and therapeutic drugs. The representative approaches for hypoxia-targeted cancer therapy are based on regulation of hypoxia inducible factor-1 causing chemoresistance and on the use of the bioreductive prodrugs which can be activated in the reductive environment of hypoxia.
For hypoxia imaging, many nitroaromatic or quinone derivatives as the hypoxia-sensitive moieties have been employed for molecular design of diagnostic agents. Of the derivatives investigated, 2-nitroimidazoles have been most widely utilized for developments of imaging agents as well as the bioreductive prodrugs because of their high sensitivity to hypoxia. Under hypoxic conditions, 2-nitroimidazoles (NIs) are changed to the hydrophilic 2-aminoimidazole via a series of selective bioreductions, which are highly reactive to the macromolecules in hypoxic tissue.
Self-assembled polymeric nanoparticles, composed of amphiphilic polymers, have emerged as a promising nanocarrier for various anticancer drugs. They exhibit unique characteristics as drug carriers, including an enhancement of drug solubility, high thermodynamic stability, and preferential accumulation into the tumor tissue via the enhanced permeation and retention (EPR) effect. Conventional nanocarriers, however, often show limited antitumor efficacy because they release the drug in a sustained manner even at the target site of action. In recent years, to enhance therapeutic efficacy, polymeric materials which respond to the tumor pathophysiological conditions have been utilized to construct the nanoparticles for drug delivery. Such stimuli-responsive nanocarriers are expected to reach the tumor site via EPR effect and release the drug rapidly when they are exposed to the tumor tissue. To date, many stimuli have been explored for development of smart nanocarriers, including ultraviolet, glutathione, pH, and temperature. Consequently, a few of the stimuli-responsive drug carriers have been advanced to the clinical trial.
However, despite the fact that hypoxia is related to various intractable diseases, a polymer that actively responds hypoxic conditions to release a drug, and nanoparticles comprising the same, have not yet been developed.